This proposal tests the hypothesis that oxidized lipoproteins induce neurodegeneration directly by acting on neurons and indirectly by activating microglia through a mechanism involving scavenger receptors. Oxidative stress mediated neuronal cell loss has been demonstrated in neurodegenerative disorders including Alzheimer's disease (AD) and stroke. Reactive oxygen species (ROS) can increase the rapid oxidation of lipids and proteins generating lipid peroxidation and oxidized protein products. Once formed, these oxidatively modified lipids and proteins may be the primary means by which ROS toxicity is elicited. High-density lipoproteins (HDLs) in the central nervous system are vulnerable to oxidative modification by trace metals, ROS, and enzymatic pathways. Preliminary data demonstrate the detrimental effects of oxidized HDL (oxHDL) on neuronal cells and the activation of microglial response in vitro. The specific aims of this proposal are: 1) To test the hypothesis that HDL induces neurodegeneration both in vitro and in vivo by activating ROS. We will characterize the neuronal and microglial response to oxHDL by activating oxidative stress, calcium and apoptotic pathways. 2) To test the hypothesis that oxHDL functions through interaction with scavenger receptors on neuronal and microglial cells. We will examine cell lines expressing scavenger receptors (SR) and cells isolated from SRgene-inactivation mice for altered response to oxHDL. 3) To test the hypothesis that the apolipoprotein E (apoE) genotype may affect the level of oxidation and the neuronal and microglial response to oxHDL. We will isolate apoE-specific HDL particles and determine their susceptibility to oxidation and their effects on neurodegeneration. 4) To test the hypothesis that oxidized HDL and scavenger receptors are present in AD brain in a regional pattern related to selective vulnerability. We will examine HDL isolated from control and AD brain for oxidative status and the relationship to apoE genotype. We will also examine the expression of SR and other molecules potentially relevant to the effects of oxHDL in the AD brain. These studies should provide insights into the normal function of HDL and SR in the CNS and in the pathogenesis of AD.